Conditions that affect components of a motor unit (motor neuron cells of the spinal cord, nerve, neuromuscular junction, and muscle fibers), sensory and autonomic nerves or their supportive structures are included in the broad category of “neuromuscular disorders”, and include peripheral neuropathies.
Motor nerves are responsible for voluntary movement. Their cell bodies lie within the spinal cord, and their processes transmit signals outward to specialized motor receptors on the skeletal muscles. Sensory nerves allow the sensation of pain, vibrations or touch, and sense where limbs are positioned in space. Their cell bodies are grouped in specialized structures called sensory “ganglia” next to the spinal cord. And they transmit signals from sensory receptors in the skin and other organs inward to the central nervous system (CNS). Autonomic nerves control involuntary functions like breathing, heartbeat, blood pressure, digestion and sexual function. Their cell bodies, clustered in autonomic ganglia, are spread throughout the body.
Neuropathy is a generic term used to describe diseases of the peripheral nervous system. There are about 200 known different causes of peripheral neuropathies. Although most neuropathies affect all three types of nerve fibers, to varying degrees, some diseases involve only one or two, and are thus said to be purely or predominantly motor, sensory, or autonomic neuropathies.
For instance, Guillain-Barré syndrome is an acute illness involving the peripheral nervous system that usually occurs two to three weeks after a flu-like disease or other infections. It is mostly a motor neuropathy, meaning that its symptoms are largely related to the involvement of the motor nerves. Despite the primarily motor nature of the disease, the earliest symptoms may be numbness and tingling felt in the lower extremities followed shortly by weakness of the distal muscles of the lower extremities. The common early symptoms reported by patients are those of tripping on the toes that later results in a footdrop. The weakness usually ascends to involve the entire lower extremities and later the upper extremities. The danger occurs when the weakness involves the muscles of respiration.
The diagnosis of Guillain-Barré syndrome is suggested when the patient presents with a history of ascending weakness and a physical examination consistent with a primarily motor neuropathy. The diagnosis is confirmed with the performance of a spinal tap, which usually shows elevation of the protein level in the spinal fluid without an increase in the number of white cells and by an electromyogram. All other conditions resembling Guillain-Barré syndrome must also be excluded.
Although Guillain-Barré syndrome is usually a self-limiting illness, intensive therapeutic intervention is often needed.
CIDP or chronic inflammatory demyelinating polyneuropathy is an immune-mediated neuropathy that affects the peripheral motor and sensory nerves. The symptoms are of a slowly progressive numbness and tingling that usually starts in the feet, but later spreads to the legs and hands. The patients also complain of some weakness, again usually starting in the lower extremities, but soon involving the upper extremities. With further involvement of the sensory system, other modalities of sensations, such as balance, are affected and the patients complain of inability to walk or maintain balance in the dark.
The diagnosis of CIDP is suspected with a history of progressive sensorimotor neuropathy. Physical examination consistent with distal sensory loss in the upper and lower extremities, in conjunction with motor weakness that can be more proximal than distal supports the clinical diagnosis. The spinal tap usually shows a significant rise in the protein level of the spinal fluid. Electromyography with nerve conduction studies also supports the diagnosis. Usually the main picture is that of slowing of the conduction velocities of the peripheral nerves. The final diagnostic step would be the performance of a nerve biopsy. Finding of inflammation on the nerve biopsy, although rare, definitely confirms the diagnosis. However, the absence of inflammation does not entirely rule it out. Findings of predominant demyelination on the nerve biopsy can be used in conjunction with the other studies and the clinical presentation to suggest a diagnosis of CIDP. Once the diagnosis is secured, treatment with immunosuppressive medications can be initiated. The first line of treatment remains high-dose steroids that are initiated orally every day and then slowly tapered over time depending on the patient's improved symptomatology. Steroid failure or intolerance to steroids necessitates the use of other immunosuppressing agents. However, better therapeutic intervention for CIDP is still a desired objective of the present invention.
Peripheral neuropathy is one of the many complications of long-standing diabetes. Usually neuropathy occurs about 8 to 10 years after the onset of diabetes. However, it is not uncommon to see patients presenting with neuropathic symptoms that have their diabetes diagnosed at that time or patients with 20 or more years of diabetes with little or no evidence of neuropathy. The symptoms of diabetic neuropathy consist of a slow and insidious numbness and tingling of the lower extremities that can progress to become a painful neuropathy. The pain is usually described as a burning sensation in the feet. Occasionally, the pain is described as a sensation of sharp, electric jolts traveling down the lower extremities. As it worsens, the pain acquires a deep bony nature. It tends to be worse at night commonly preventing or awakening the patients from sleep. As the neuropathy worsens, it affects the upper extremities and may involve the motor nerves with the complaint of weakness in the distal muscles of the legs and arms. The neuropathy of diabetes can also involve the autonomic nervous system causing problems with sweating, blood pressure, and sexual function.
Diabetic neuropathy is suspected when the patient's history and physical examination are compatible with the clinical picture in a setting of diabetes. In the absence of the history of diabetes, diagnostic tests to rule out diabetes is required. The workup is completed by the performance of an electromyogram with nerve conduction studies to quantitate the extent of involvement of the peripheral nervous system.
Diabetic neuropathy, unfortunately, has no effective treatment at this point in the art. Adequate control of the patient's blood sugar, however, has been shown to slow the progression of the symptoms. Symptomatic treatment with various medications that suppress neuropathic pain, including Elavil, Tegretol and more recently Ultram, have been successful. Thus, a more effective treatment for diabetic neuropathy is an objective of the present invention.
Other common causes of neuropathy such include alcoholism or medication induced neuropathies, neuropathies resulting from trauma, such as crushed nerves, as well as inherited forms of such disorders.